Reciprocal activation between MMP-8 and TGF-ß1 stimulates EMT and malignant progression of hepatocellular carcinoma.

The efficiency of surgery in hepatocellular carcinoma (HCC) is limited due to metastasis and recurrence, but the molecular mechanisms are unclear. Here, we show that MMP-8 and TGF-ß1 accumulate in highly invasive HCC cell lines and invasive HCC patient tissues. Upregulation of MMP-8 and TGF-ß1 correlated with changes in cellular epithelial-mesenchymal transition (EMT) phenotypes and HCC migration and invasion. The expression of TGF-ß1 was markedly restored by MMP-8 overexpression in TGF-ß1-depleted HCC cells mainly via the activation of PI3K/Akt/Rac1 pathway. Similarly, the expression of MMP-8 was restored by TGF-ß1 treatment in MMP-8-depleted HCC cells mainly through the activation of the same PI3K/Akt/Rac1 pathway. MMP-8 expression was significantly related to TGF-ß1 expression in HCC patient tissues, and high expression of MMP-8 or TGF-ß1 was significantly associated with TNM stage and HCC metastasis. Specifically, patients with high co-expression of MMP-8 and TGF-ß1 had a shorter time-to-recurrence than those with low co-expression. Therefore, the reciprocal positive interplay between MMP-8 and TGF-ß1 contributes to HCC invasion and metastasis by inducing EMT mainly through the PI3K/Akt/Rac1 pathway.